ANGIOTENSIN-II INDUCES DELAYED MITOGENESIS AND CELLULAR PROLIFERATIONIN RAT AORTIC SMOOTH-MUSCLE CELLS - CORRELATION WITH THE EXPRESSION OF SPECIFIC ENDOGENOUS GROWTH-FACTORS AND REVERSAL BY SURAMIN

By means of a rat aortic smooth muscle (RASM) cell culture model, the effects of angiotensin II (AII) on early proto-oncogene gene expressio n, DNA synthesis, and cell proliferation were measured and compared to known mitogens. In 24-h [H-3]thymidine incorporation assays, AII was found to be a weak mitogen when compared to potent mitogens such as fe tal bovine serum and platelet-derived growth factor(PDGF). In contrast , when assays were carried out for 48 h, AII induced a significant dos e-dependent stimulation of DNA synthesis, which more than doubled at 3 nM AII, and was maximal (five- to eightfold above control) at 100 nM AII. Treatment of cells with the AII type 1 receptor antagonist losart an inhibited the mitogenic effects of AII. AII also stimulated smooth muscle cell proliferation, as indicated by an absolute increase in cel l number after AII stimulation of RASM cells for 5 d. AII stimulation of RASM cell growth correlated with the increased expression of specif ic endogenous growth factors, including transforming growth factor bet a(1) (TGF-beta(1)) and PDGF A-chain. However, addition of either PDGF- or TGF-beta(1)-neutralizing antibodies failed to significantly reduce the delayed mitogenic effects induced by AII. In contrast, we found t hat AII-stimulated mitogenesis could be inhibited in a dose-dependent manner by the growth factor inhibitor drug suramin. Taken together, ou r results indicate that enhanced endogenous growth factor expression m ay represent the direct mechanism by which AII promotes smooth muscle cell growth in some vascular hyperproliferative diseases.